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Review
. 2013 Mar;93(3):329-42.
doi: 10.1189/jlb.0912437. Epub 2012 Nov 7.

Current trends in inflammatory and immunomodulatory mediators in sepsis

Monowar Aziz  1 , Asha Jacob, Weng-Lang Yang, Akihisa Matsuda, Ping Wang
Affiliations
Review

Current trends in inflammatory and immunomodulatory mediators in sepsis

Monowar Aziz et al. J Leukoc Biol. 2013 Mar.

Abstract

Sepsis refers to severe systemic inflammation in response to invading pathogens. An overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides, and cell stress markers play key roles in sepsis pathophysiology. Various adhesion molecules and chemokines sequester and activate neutrophils into the target organs, further augmenting inflammation and tissue damage. Although the anti-inflammatory substances counterbalance proinflammatory mediators, prolonged immune modulation may cause host susceptibility to concurrent infections, thus reflecting enormous challenge toward developing effective clinical therapy against sepsis. To understand the complex interplay between pro- and anti-inflammatory phenomenon in sepsis, there is still an unmet need to study newly characterized mediators. In addition, revealing the current trends of novel mediators will upgrade our understanding on their signal transduction, cross-talk, and synergistic and immunomodulating roles during sepsis. This review highlights the latest discoveries of the mediators in sepsis linking to innate and adaptive immune systems, which may lead to resolution of many unexplored queries.

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Figures

Figure 1.
Figure 1.. Roles of innate and adaptive immune system in sepsis pathophysiology.
(A) In response to invading pathogens, macrophages serve as the first line of defense, inducing the innate-immune response. Proinflammatory cytokines, e.g., TNF-α, IL-1β, and IL-6, as released from macrophages, further augment systemic inflammation and epithelial barrier dysfunction, whereas the anti-inflammatory cytokines, such as IL-10 and TGF-β, counterbalance excessive immune responses. Bacterial pathogens and systemic inflammatory mediators also promote epithelial barrier disruption to exaggerate inflammation and induce the expression of ICAM-1. The chemokines, such as IL-8 and MCP-1, released from macrophages, activate and promote neutrophil migration toward the site of inflammation, as well as to the remote organs. Excessive neutrophil infiltration exaggerates inflammation and severe organ injury by releasing several proinflammatory mediators, e.g., MPO, NO, ROS, TNF-α, and IL-6. (B) Immature DCs transform into its mature form upon interacting with the pathogen and serve as professional APCs to activate the adaptive immune system by promoting T cell functions through antigen presentation. Macrophages can also act as APCs to ingest, process, and present pathogens to T cells and promote their activation and differentiation. Activated T cells further differentiate into its lineages, generating distinct cytokine profiles, which include Th1: IL-2, TNF-α, and IFN-γ; Th2: IL-4, IL-5, and IL-10; and Th17: IL-17. DCs can also be activated by pathogens to trigger innate-immune functions by producing pro- and anti-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-10, and TGF-β. In sepsis, immune cells undergo apoptosis, leading to an immunosuppressive environment.
Figure 2.
Figure 2.. Latest trends in sepsis mediators.
In sepsis, the newly identified mediators are categorized into immunostimulatory, which includes IL-22, ET-1, S1P, resistin, IL-17, visfatin, HMGB1, OPN, and histone, and immunomodulatory, such as IL-33, ghrelin, AM/AMBP-1, adiponectin, RvD2, and MFG-E8, depending on their roles in exaggerating or regulating immune functions. Immunostimulatory mediators act on macrophages (Mϕ), DCs, neutrophils, lymphocytes, and epithelial cells to augment the production of proinflammatory cytokines, e.g., TNF-α, IL-1β, IL-6, IFN-γ, IL-2, IL-4, IL-5, IL-17 and chemokines, e.g., IL-8 and MCP-1, which exert profound effects on neutrophil activation and migration in various organs. On the other hand, IL-10 exhibits immune-regulatory roles to control excessive production of proinflammatory cytokines. As IL-10 has been considered a “negative” regulator in sepsis, it is shown in the yellow-filled box to be distinguished from other Th2 cytokines. Excessive neutrophil infiltration releases ROS and MPO, leading to multiple organ injuries. On the other hand, novel immunomodulatory substances attract neutrophils at the infectious area, promote bacterial clearance, attenuate systemic inflammation, reduce neutrophil infiltration at various organs, and improve survival in sepsis.
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